Meta-analysis of the efficacy and safety of bispecific antibodies in immune therapy for lung cancer.
Metaanálisis de la eficacia y la seguridad de los anticuerpos específicos en la inmunoterapia del cáncer de pulmón.
Keywords:
Antibodies, Bispecific, Lung cancer, Immunotherapy, Meta-Analysis, Efficacy, Safety
Abstract
This work evaluates the efficacy and safety of bispecific antibod- ies (BsAbs) in lung cancer immunotherapy through a meta-analysis, providing more comprehensive evidence for their clinical application. A systematic search was conducted in PubMed, Embase, Cochrane Library, and various Chinese databases to identify eligible randomized controlled trials and quasi-randomized controlled trials. Clinical data on bispecific antibody therapy for lung cancer were collected. The primary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and the incidence of immune-related adverse events (irAEs). Data analysis was performed using Rev- Man 5.3 software, with fixed-effect or random-effects models. Nine studies were included, with a total sample size of 588 patients. The meta-analysis revealed no statistically significant differences between the bispecific antibody group and the traditional treatment group in ORR, OS and PFS, with combined effect sizes of odds ratio (OR)=1.31 and 95% confidence interval (CI)=0.98-1.76, OR=1.36 and 95%CI=0.99-1.87 and OR=1.07 and 95%CI=0.80-1.43, respectively (p 0.07, 0.06, and 0.64, respectively). However, the incidence of irAEs was significantly lower in the bispecific antibody group (OR = 1.56; p = 0.0007), indicating a reduction in such events. Bispecific antibodies demonstrate good safety in lung cancer immunotherapy, particularly in reducing irAEs. Despite some improvements in efficacy (e.g., ORR and OS), BsAbs do not demonstrate a significant superiority over conventional treatments.
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References
Khosla AA, Jatwani K, Singh R, Reddy A, Jaiyesimi I, Desai A. Bispecific Antibodies in Lung Cancer: A State-of-the- Art Review. Pharmaceuticals (Basel). 2023;16(10):1461. https://doi.org/10.3390/ph16101461
Kalinka E, Wojas-Krawczyk K, Kraw- czyk P. Double Guard Efficiency and Safety-Overcoming Resistance to Immunotherapy by Blocking or Stimulating Several Immune Checkpoints in Non-Small Cell Lung Cancer Patients. Cancers (Basel). 2023;15(13):3499. https://doi.org/10.3390/cancers15133499.
Dahlén E, Veitonmäki N, Norlén P. Bi-specific antibodies in cancer immune-therapy. Ther Adv Vaccines Immunother. 2018;6(1):3-17. https://doi.org/10.1177/2515135518763280.
Zhang B, Li W, Fan D, Tian W, Zhou J, Ji Z, Song Y. Advances in the study of CD47- based bispecific antibody in cancer immu-notherapy. Immunology. 2022;167(1):15-27. https://doi.org/10.1111/imm.13498.
Krishnamurthy A, Jimeno A. Bispecific antibodies for cancer therapy: A review. Pharmacol Ther. 2018;185:122-134. https://doi.org/10.1016/j.pharmthera.2017.12.002.
Li T, Niu M, Zhou J, Wu K, Yi M. The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling. Cell Commun Signal. 2024;22(1):179. https://doi.org/10.1186/s12964-024-01562-5.
Wang W, Qiu T, Li F, Ren S. Current status and future perspectives of bispecific antibodies in the treatment of lung cancer. Chin Med J (Engl). 2023;136(4):379-393. https://doi.org/10.1097/CM9.0000000000002460.
Chames P, Baty D. Bispecific antibodies for cancer therapy: the light at the end of the tunnel? MAbs. 2009; 1(6): 539-547. https://doi.org/10.4161/mabs.1.6.10015.
Ordóñez-Reyes C, Garcia-Robledo JE, Chamorro DF, Mosquera A, Sussmann L, Ruiz-Patiño A, et al. Bispecific Antibodies in Cancer Immunotherapy: A Novel Response to an Old Question. Pharmaceutics. 2022;14(6):1243. https://doi.org/10.3390/pharmaceutics14061243.
Klein C, Brinkmann U, Reichert JM, Kontermann RE. The present and future of bispecific antibodies for cancer therapy. Nat Rev Drug Discov. 2024;23(4):301-319. https://doi.org/10.1038/s41573-024-00896-6.
Wu Y, Yi M, Zhu S, Wang H, Wu K. Recent advances and challenges of bispecific antibodies in solid tumors. Exp Hematol Oncol. 2021;10(1):56. https://doi.org/10.1186/s40164-021-00250-1.
Nejadghaderi SA, Balibegloo M, Noori M, Fayyaz F, Saghazadeh A, Rezaei N. Clinical efficacy and safety of bispecific antibodies for the treatment of solid tumors: a systematic review and meta-analysis. Expert Rev Anticancer Ther. 2023;23(3):307- 318. https://doi.org/10.1080/14737140.2023.2183847.
Cheng L, Chen L, Shi Y, Gu W, Ding W, Zheng X, et al. Efficacy and safety of bi- specific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison. Mol Cancer. 2024;23(1):77. https://doi.org/10.1186/s12943-024-01956-6.
Xiong A, Li W, Li X, Fan Y, Ma Z, Fang J, et al. Efficacy and safety of KN046, a novel bispecific antibody against PD-L1 and CTLA-4, in patients with non-small cell lung cancer who failed platinum-based chemotherapy: a phase II study. Eur J Cancer. 2023;190:112936. https://doi.org/10.1016/j.ejca.2023.05.024.
Zhao Y, Chen G, Chen J, Zhuang L, Du Y, Yu Q, et al. AK112, a novel PD-1/VEGF bispecific antibody, in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): an open-label, multicenter, phase II trial. EClinicalMedicine. 2023;62:102106. https://doi.org/10.1016/j.eclinm.2023.102106
Hellmann MD, Bivi N, Calderon B, Shimizu T, Delafontaine B, Liu ZT, et al. Safety and Immunogenicity of LY3415244, a Bispecific Antibody Against TIM-3 and PD-L1, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2021;27(10):2773- 2781. https://doi.org/10.1158/1078-0432.CCR-20-3716.
Liu D, Gong J, Li J, Qi C, Niu Z, Liu B, et al. Efficacy and safety of KN026, a bispecific anti-HER2 antibody, in combination with KN046, an anti-TLA4/PD-L1 antibody, in patients with advanced HER2-positive nonbreast cancer: a combined analysis of a phase Ib and a phase II study. Signal Transduct Target Ther. 2025;10(1):104. https://doi.org/10.1038/s41392-025-02195-x.
Li H, Zhao W, Li C, Shen H, Li M, Wang C, et al. The efficacy and safety of a novel PD-1/CTLA-4 bispecific antibody cadonilimab (AK104) in advanced non-small cell lung cancer: A multicenter retrospective observational study. Thorac Cancer. 2024;15(32):2327-2338. https://doi.org/10.1111/1759-7714.15455.
Chen X, Amar N, Zhu Y, Wang C, Xia C, Yang X, et al. Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth. J Immunother Cancer. 2020;8(1):e000785. https://doi.org/10.1136/jitc-2020-000785.
Yap TA, LoRusso PM, Wong DJ, Hu-Lieskovan S, Papadopoulos KP, Holz JB, et al. A Phase 1 First-in-Human Study of FS118, a Tetravalent Bispecific Antibody Targeting LAG-3 and PD-L1 in Patients with Advanced Cancer and PD-L1 Resistance. Clin Cancer Res. 2023;29(5):888-898. https://doi.org/10.1158/1078-0432.CCR-22-1449.
Ma Y, Xue J, Zhao Y, Zhang Y, Huang Y, Yang Y, et al Phase I trial of KN046, a novel bispecific antibody targeting PD- L1 and CTLA-4 in patients with advanced solid tumors. J Immunother Cancer. 2023;11(6):e006654. https://doi.org/10.1136/jitc-2022-006654.
Song X, Xiong A, Wu F, Li X, Wang J, Jiang T, et al. Spatial multi-omics revealed the impact of tumor ecosystem heterogeneity on immunotherapy efficacy in patients with advanced non-small cell lung cancer treated with bispecific antibody. J Immunother Cancer. 2023;11(2):e006234. https://doi.org/10.1136/jitc-2022-006234.
Wei J, Yang Y, Wang G, Liu M. Current landscape and future directions of bispecific antibodies in cancer immunotherapy. Front Immunol. 2022;13:1035276. https://doi.org/10.3389/fimmu.2022.1035276.
Zhang T, Lin Y, Gao Q. Bispecific antibodies targeting immunomodulatory checkpoints for cancer therapy. Cancer Biol Med. 2023;20(3):181–195.
https://doi.org/10.20892/j.issn.2095-3941.2023.0002.
Sun Y, Yu X, Wang X, Yuan K, Wang G, Hu L, et al. Bispecific antibodies in cancer therapy: Target selection and regulatory requirements. Acta Pharm Sin B. 2023;13(9):3583-3597. https://doi.org/10.1016/j.apsb.2023.05.023.
Chen B, Yao W, Li X, Lin G, Chu Q, Liu H, et al A phase Ib/II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus anlotinib as first-line treatment in patients with advanced non-small cell lung cancer. Br J Cancer. 2024;130(3):450- 456. https://doi.org/10.1038/s41416-023-02519-0.
Ruan DY, Wei XL, Liu FR, Hu XC, Zhang J, Ji DM, et al. The first-in-class bispecific antibody IBI318 (LY3434172) targeting PD-1 and PD-L1 in patients with advanced tumors: a phase Ia/Ib study. J Hematol Oncol. 2024;17(1):118. https://doi.org/10.1186/s13045-024-01644-4.
Rader C. Bispecific antibodies in cancer immunotherapy. Curr Opin Biotechnol. 2020;65:9-16. https://doi.org/10.1016/j.copbio.2019.11.020.
Yu S, Li A, Liu Q, Yuan X, Xu H, Jiao D, et al. Recent advances of bispecific anti-bodies in solid tumors. J Hematol Oncol. 2017;10(1):155. https://doi.org/10.1186/s13045-017-0522-z.
Wang S, Chen K, Lei Q, Ma P, Yuan AQ, Zhao Y, et al. The state of the art of bispecific antibodies for treating human malignancies. EMBO Mol Med. 2021;13(9):e14291. https://doi.org/10.15252/emmm.202114291.
Koopmans I, Hendriks MAJM, van Ginkel RJ, Samplonius DF, Bremer E, Helfrich W. Bispecific Antibody Approach for Improved Melanoma-Selective PD-L1 Immune Checkpoint Blockade. J Invest Dermatol. 2019;139(11):2343-2351.e3. https://doi.org/10.1016/j.jid.2019.01.038.
Rohrberg K S, Brandão M, Castanon Alvarez E, Felip E, Gort E H, Hiltermann T JJN, et al. Safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AZD2936, a bispecific antibody targeting PD-1 and TIGIT, in checkpoint inhibitor (CPI)-experienced advanced/ metastatic non-small-cell lung cancer (NSCLC): First report of ARTEMIDE-01. J Clin Oncol. 2023; 41(16). https://doi.org/10.1200/jco.2023.41.16_suppl.9050.
Xiong A, Wang L, Chen J, Wu L, Liu B, Yao J, et al. Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China. Lancet. 2025;405(10481):839-849. https://doi.org/10.1016/S0140-6736(24)02722-3.
HARMONi-A Study Investigators; Fang W, Zhao Y, Luo Y, Yang R, Huang Y, et al. Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer with EGFR Variant: A Randomized Clinical Trial. JAMA. 2024;332(7):561-570. https://doi.org/10.1001/jama.2024.10613.
Mountzios G, Sun L, Cho BC, Demirci U, Baka S, Gümüş M, et al. Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy. N Engl J Med. 2025;393(4):349-361. https://doi.org/10.1056/NEJMoa2502099.
Kalinka E, Wojas-Krawczyk K, Kraw- czyk P. Double Guard Efficiency and Safety-Overcoming Resistance to Immunotherapy by Blocking or Stimulating Several Immune Checkpoints in Non-Small Cell Lung Cancer Patients. Cancers (Basel). 2023;15(13):3499. https://doi.org/10.3390/cancers15133499.
Dahlén E, Veitonmäki N, Norlén P. Bi-specific antibodies in cancer immune-therapy. Ther Adv Vaccines Immunother. 2018;6(1):3-17. https://doi.org/10.1177/2515135518763280.
Zhang B, Li W, Fan D, Tian W, Zhou J, Ji Z, Song Y. Advances in the study of CD47- based bispecific antibody in cancer immu-notherapy. Immunology. 2022;167(1):15-27. https://doi.org/10.1111/imm.13498.
Krishnamurthy A, Jimeno A. Bispecific antibodies for cancer therapy: A review. Pharmacol Ther. 2018;185:122-134. https://doi.org/10.1016/j.pharmthera.2017.12.002.
Li T, Niu M, Zhou J, Wu K, Yi M. The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling. Cell Commun Signal. 2024;22(1):179. https://doi.org/10.1186/s12964-024-01562-5.
Wang W, Qiu T, Li F, Ren S. Current status and future perspectives of bispecific antibodies in the treatment of lung cancer. Chin Med J (Engl). 2023;136(4):379-393. https://doi.org/10.1097/CM9.0000000000002460.
Chames P, Baty D. Bispecific antibodies for cancer therapy: the light at the end of the tunnel? MAbs. 2009; 1(6): 539-547. https://doi.org/10.4161/mabs.1.6.10015.
Ordóñez-Reyes C, Garcia-Robledo JE, Chamorro DF, Mosquera A, Sussmann L, Ruiz-Patiño A, et al. Bispecific Antibodies in Cancer Immunotherapy: A Novel Response to an Old Question. Pharmaceutics. 2022;14(6):1243. https://doi.org/10.3390/pharmaceutics14061243.
Klein C, Brinkmann U, Reichert JM, Kontermann RE. The present and future of bispecific antibodies for cancer therapy. Nat Rev Drug Discov. 2024;23(4):301-319. https://doi.org/10.1038/s41573-024-00896-6.
Wu Y, Yi M, Zhu S, Wang H, Wu K. Recent advances and challenges of bispecific antibodies in solid tumors. Exp Hematol Oncol. 2021;10(1):56. https://doi.org/10.1186/s40164-021-00250-1.
Nejadghaderi SA, Balibegloo M, Noori M, Fayyaz F, Saghazadeh A, Rezaei N. Clinical efficacy and safety of bispecific antibodies for the treatment of solid tumors: a systematic review and meta-analysis. Expert Rev Anticancer Ther. 2023;23(3):307- 318. https://doi.org/10.1080/14737140.2023.2183847.
Cheng L, Chen L, Shi Y, Gu W, Ding W, Zheng X, et al. Efficacy and safety of bi- specific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison. Mol Cancer. 2024;23(1):77. https://doi.org/10.1186/s12943-024-01956-6.
Xiong A, Li W, Li X, Fan Y, Ma Z, Fang J, et al. Efficacy and safety of KN046, a novel bispecific antibody against PD-L1 and CTLA-4, in patients with non-small cell lung cancer who failed platinum-based chemotherapy: a phase II study. Eur J Cancer. 2023;190:112936. https://doi.org/10.1016/j.ejca.2023.05.024.
Zhao Y, Chen G, Chen J, Zhuang L, Du Y, Yu Q, et al. AK112, a novel PD-1/VEGF bispecific antibody, in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): an open-label, multicenter, phase II trial. EClinicalMedicine. 2023;62:102106. https://doi.org/10.1016/j.eclinm.2023.102106
Hellmann MD, Bivi N, Calderon B, Shimizu T, Delafontaine B, Liu ZT, et al. Safety and Immunogenicity of LY3415244, a Bispecific Antibody Against TIM-3 and PD-L1, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2021;27(10):2773- 2781. https://doi.org/10.1158/1078-0432.CCR-20-3716.
Liu D, Gong J, Li J, Qi C, Niu Z, Liu B, et al. Efficacy and safety of KN026, a bispecific anti-HER2 antibody, in combination with KN046, an anti-TLA4/PD-L1 antibody, in patients with advanced HER2-positive nonbreast cancer: a combined analysis of a phase Ib and a phase II study. Signal Transduct Target Ther. 2025;10(1):104. https://doi.org/10.1038/s41392-025-02195-x.
Li H, Zhao W, Li C, Shen H, Li M, Wang C, et al. The efficacy and safety of a novel PD-1/CTLA-4 bispecific antibody cadonilimab (AK104) in advanced non-small cell lung cancer: A multicenter retrospective observational study. Thorac Cancer. 2024;15(32):2327-2338. https://doi.org/10.1111/1759-7714.15455.
Chen X, Amar N, Zhu Y, Wang C, Xia C, Yang X, et al. Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth. J Immunother Cancer. 2020;8(1):e000785. https://doi.org/10.1136/jitc-2020-000785.
Yap TA, LoRusso PM, Wong DJ, Hu-Lieskovan S, Papadopoulos KP, Holz JB, et al. A Phase 1 First-in-Human Study of FS118, a Tetravalent Bispecific Antibody Targeting LAG-3 and PD-L1 in Patients with Advanced Cancer and PD-L1 Resistance. Clin Cancer Res. 2023;29(5):888-898. https://doi.org/10.1158/1078-0432.CCR-22-1449.
Ma Y, Xue J, Zhao Y, Zhang Y, Huang Y, Yang Y, et al Phase I trial of KN046, a novel bispecific antibody targeting PD- L1 and CTLA-4 in patients with advanced solid tumors. J Immunother Cancer. 2023;11(6):e006654. https://doi.org/10.1136/jitc-2022-006654.
Song X, Xiong A, Wu F, Li X, Wang J, Jiang T, et al. Spatial multi-omics revealed the impact of tumor ecosystem heterogeneity on immunotherapy efficacy in patients with advanced non-small cell lung cancer treated with bispecific antibody. J Immunother Cancer. 2023;11(2):e006234. https://doi.org/10.1136/jitc-2022-006234.
Wei J, Yang Y, Wang G, Liu M. Current landscape and future directions of bispecific antibodies in cancer immunotherapy. Front Immunol. 2022;13:1035276. https://doi.org/10.3389/fimmu.2022.1035276.
Zhang T, Lin Y, Gao Q. Bispecific antibodies targeting immunomodulatory checkpoints for cancer therapy. Cancer Biol Med. 2023;20(3):181–195.
https://doi.org/10.20892/j.issn.2095-3941.2023.0002.
Sun Y, Yu X, Wang X, Yuan K, Wang G, Hu L, et al. Bispecific antibodies in cancer therapy: Target selection and regulatory requirements. Acta Pharm Sin B. 2023;13(9):3583-3597. https://doi.org/10.1016/j.apsb.2023.05.023.
Chen B, Yao W, Li X, Lin G, Chu Q, Liu H, et al A phase Ib/II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus anlotinib as first-line treatment in patients with advanced non-small cell lung cancer. Br J Cancer. 2024;130(3):450- 456. https://doi.org/10.1038/s41416-023-02519-0.
Ruan DY, Wei XL, Liu FR, Hu XC, Zhang J, Ji DM, et al. The first-in-class bispecific antibody IBI318 (LY3434172) targeting PD-1 and PD-L1 in patients with advanced tumors: a phase Ia/Ib study. J Hematol Oncol. 2024;17(1):118. https://doi.org/10.1186/s13045-024-01644-4.
Rader C. Bispecific antibodies in cancer immunotherapy. Curr Opin Biotechnol. 2020;65:9-16. https://doi.org/10.1016/j.copbio.2019.11.020.
Yu S, Li A, Liu Q, Yuan X, Xu H, Jiao D, et al. Recent advances of bispecific anti-bodies in solid tumors. J Hematol Oncol. 2017;10(1):155. https://doi.org/10.1186/s13045-017-0522-z.
Wang S, Chen K, Lei Q, Ma P, Yuan AQ, Zhao Y, et al. The state of the art of bispecific antibodies for treating human malignancies. EMBO Mol Med. 2021;13(9):e14291. https://doi.org/10.15252/emmm.202114291.
Koopmans I, Hendriks MAJM, van Ginkel RJ, Samplonius DF, Bremer E, Helfrich W. Bispecific Antibody Approach for Improved Melanoma-Selective PD-L1 Immune Checkpoint Blockade. J Invest Dermatol. 2019;139(11):2343-2351.e3. https://doi.org/10.1016/j.jid.2019.01.038.
Rohrberg K S, Brandão M, Castanon Alvarez E, Felip E, Gort E H, Hiltermann T JJN, et al. Safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AZD2936, a bispecific antibody targeting PD-1 and TIGIT, in checkpoint inhibitor (CPI)-experienced advanced/ metastatic non-small-cell lung cancer (NSCLC): First report of ARTEMIDE-01. J Clin Oncol. 2023; 41(16). https://doi.org/10.1200/jco.2023.41.16_suppl.9050.
Xiong A, Wang L, Chen J, Wu L, Liu B, Yao J, et al. Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China. Lancet. 2025;405(10481):839-849. https://doi.org/10.1016/S0140-6736(24)02722-3.
HARMONi-A Study Investigators; Fang W, Zhao Y, Luo Y, Yang R, Huang Y, et al. Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer with EGFR Variant: A Randomized Clinical Trial. JAMA. 2024;332(7):561-570. https://doi.org/10.1001/jama.2024.10613.
Mountzios G, Sun L, Cho BC, Demirci U, Baka S, Gümüş M, et al. Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy. N Engl J Med. 2025;393(4):349-361. https://doi.org/10.1056/NEJMoa2502099.
Published
2026-03-05
How to Cite
Zhao, X., & Liu, Y. (2026). Meta-analysis of the efficacy and safety of bispecific antibodies in immune therapy for lung cancer.: Metaanálisis de la eficacia y la seguridad de los anticuerpos específicos en la inmunoterapia del cáncer de pulmón. Investigación Clínica, 67(1), 139-151. https://doi.org/10.54817/IC.v67n1a10
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